News Release

Are we mice or men? Gene mutation linked to improving heart failure in mice proves lethal in humans

Peer-Reviewed Publication

JCI Journals

The goal of molecular medicine is to utilize the wealth of available experimental tools to develop treatments for human disease. Researchers develop animal models of a disease, investigate the underlying biological mechanisms, and conceive and test novel therapies until a successful treatment is found. The treatment strategy is then developed for human trial.

However, what if the outcome of the treatment was profoundly different in humans when compared with mice? Are we failing to consider the critical differences between mouse and man? Two studies published in the March 14 issue of the Journal of Clinical Investigation led by Evangelia Kranias and researchers at the University of Cincinnati reveal that a mutation in the human gene encoding the protein phospholamban (PLN) is linked to heart failure. In striking contrast to previous reports that indicate that "knock-out" or inhibition of PLN is beneficial in mouse models of heart failure, the researchers reveal that humans with mutated forms of PLN develop lethal heart failure.

Heart failure is a leading cause of human morbidity and mortality worldwide and costs close to $18 billion in health-care–related costs in America each year. Characterized by suppressed calcium cycling in the heart, it impairs the ability of the heart to supply adequate oxygen- and nutrient-rich blood to the body. Calcium regulates the contraction and relaxation of heart muscle and PLN acts to halt calcium cycling at the end of the contraction so that muscles may relax between beats.

Recent experimental successes in mice have generated much enthusiasm for treating an array of conditions that ultimately result in heart failure by "knocking-out" the PLN gene and thereby enhancing calcium cycling.

However, the effect of inhibiting PLN in cases of cardiac hypertrophy (which can progress to heart failure) was unknown.

In the first study, the researchers studied two mouse models of cardiac hypertrophy in which mice destined to develop cardiac hypertrophy were also genetically modified to lack the PLN gene. They found that the absence of the PLN gene restored impaired calcium signaling and muscle contraction in individual heart cells, however there was no reversal or prevention of hypertrophy of the whole heart.

In the second study, the authors found that individuals with naturally occurring mutations in the human PLN gene develop heart failure. Individuals that lacked the PLN gene suffered fatal heart failure. The results indicate that PLN is essential for cardiac health in humans and its absence is lethal – the direct opposite of the results observed in mice.

In contrast to earlier successful studies in mice in which genetic manipulation was able to prevent or reverse heart failure, "these two studies provide a sobering reminder of heart failure's complexity" writes Jonathon Lederer, a heart specialist at the University of Maryland Biotechnology Institute. "By examining both animal models and human disease, these papers indicate that the role of PLN in the pathogenesis of heart failure might be more complicated than previously thought". The two studies also indicate that we need to better understand inherent differences in cardiac physiology between mice and humans. Dr. Kranias concluded that "these data emphasize a general concern that targeted therapies whose design is based exclusively on results of studies in rodent models, in which phenotypes can differ radically from those observed in the corresponding human genetic condition, may not ultimately be successful in human disease.

CONTACT:
Evangelia G. Kranias
University of Cincinnati Medical Center
Dept Of Pharmacology & Cell Biophysics
231 Albert Sabin Way
ML 0575
Cincinnati, OH 45267-0575
USA
Phone 1-513-558-2377
Fax 1-513-558-2269
E-mail: Litsa.Kranias@uc.edu

View the PDF of the first article at: http://www.jci.org/cgi/content/full/111/6/859

ACCOMPANYING COMMENTARY: The challenge of molecular medicine: Complexity versus Occam's Razor

CONTACT: W. Jonathon Lederer
Dept. Of Physiology
Univ. Of Maryland School Of Medicine
660 W. Redwood St.
Baltimore, MD 21201
USA
Phone 1-410-706-3852
Fax 1-410-706-8341
E-mail: jlederer@umaryland.edu

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